Radiofrequency Thermal Ablation for Hepatocellular Carcinoma Stimulates Autologous NK-Cell Response

doi:10.1053/j.gastro.2009.12.051

Gastroenterology

Volume 138, Issue 5, May 2010, Pages 1931-1942.e2

https://doi.org/10.1053/j.gastro.2009.12.051 Get rights and content

Background & Aims

Radiofrequency thermal ablation (RFA) is a minimally invasive technique used as standard local therapy of hepatocellular carcinoma and second-line treatment for metastatic liver tumors. Studies in preclinical models and in patients have shown that thermal destruction of tumor tissue can enhance anti-tumor cellular responses, but our knowledge of its impact on natural killer (NK) cells is still very limited.

Methods

Thirty-seven patients undergoing RFA for hepatocellular carcinoma were studied for peripheral blood lymphocytes counts followed by phenotypic and functional characterization of NK-cell population.

Results

Peripheral blood lymphocytes kinetics revealed an increased frequency and absolute number of NK cells expressing higher levels of activatory along with reduced levels of inhibitory NK receptors, and increased functional NK-cell activity. A prevalent expansion of the CD3⁻CD56^dim NK subset was observed compared to the CD3⁻CD56^bright counterpart. Interferon-γ production, anti-K562 cell cytotoxicity, and antibody-dependent cell cytotoxicity, appeared consistently increased in terms of both absolute activity and killing efficiency at 4 weeks after RFA, as compared to baseline. Interestingly, when recurrence-free survival was assessed in 2 groups of patients separated according to higher vs lower enhancement of cytotoxicity and/or interferon-γ production, a significant difference was observed, thus suggesting a potential predictive role of NK functional assays on efficacy of RFA.

Conclusions

RFA can lead to stimulation of NK cells with a more differentiated and proactivatory phenotypic profile with general increase of functional activities. This observation may be relevant for development of adjuvant immunotherapeutic strategies aimed at enhancing NK-cell responses against primary and metastatic liver tumors.

Section snippets

Patients

Thirty-seven patients undergoing RFA for HCC in liver cirrhosis were studied (Table 1). Hepatocellular carcinoma diagnosis was defined by concordant ultrasounds and contrast-enhanced computed tomography (CT). All patients were treated for a single HCC nodule, with the exception of patients 1, 2, 6, 8, 16, 25, 31, 35, who were treated for 2 or 3 nodules; HCC size ranged between 1.5 and 4.5 cm in diameter. Liver cirrhosis was due to hepatitis C virus infection in 26 patients, to hepatitis B virus

RFA is Associated With Increase of Circulating NK Cells

In order to assess whether radiofrequency thermal ablation can alter the homeostasis of lymphocyte populations circulating in peripheral blood, the absolute numbers of B cells, T cells, CD4⁺, and CD8⁺ T-cell subsets, and NK cells were evaluated directly in red-cell lysed whole-blood samples drawn the day before as well as 1 week and 4 weeks after RFA. A significant increase in the absolute number of circulating NK cells was observed consistently at both time points after treatment (Figure 1A).

Discussion

Results from this study demonstrate that RFA treatment of liver nodules in HCC patients increases the pool of NK lymphocytes circulating in peripheral blood. The effect of RFA did not appear simply limited to peripheral mobilization because relevant aspects of the NK population, including the subsets composition, expression of activatory and inhibitory receptors, direct as well as indirect IgG-mediated cytotoxicity, and potential for IFN-γ secretion, were also significantly and consistently

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: Conflicts of interest The authors disclose no conflicts.

: Funding The study was supported by Fondazione Cassa di Risparmio di Parma and by Ministry of Health, Programma Straordinario Ricerca Oncologica 2006.

View full text

Basic—Liver, Pancreas, and Biliary TractRadiofrequency Thermal Ablation for Hepatocellular Carcinoma Stimulates Autologous NK-Cell Response

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients

RFA is Associated With Increase of Circulating NK Cells

Discussion

The current role of radiofrequency ablation in the management of hepatocellular carcinoma: a systematic review

Ann Surg

Radiofrequency ablation in metastatic disease

Recent Results Cancer Res

Five-year survival in 309 patients with colorectal liver metastases treated with radiofrequency ablation

Eur Radiol

Laser hypertermia and radiofrequency ablation of hepatic lesions

Semin Intervent Radiol

Heat shock protein expression induced by percutaneous radiofrequency ablation of hepatocellular carcinoma in vivo

Int J Oncol

Expression of heat shock proteins in human hepatocellular carcinoma after radiofrequency ablation in an animal model

Oncol Rep

Immunoregulatory effects of liver ablation therapies for the treatment of primary and metastatic liver malignancies

Liver Int

The endoplasmic reticulum-resident heat shock protein Gp96 activates dendritic cells via the Toll-like receptor 2/4 pathway

Biol Chem

Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex

J Immunol

Dissecting the role of hyperthermia in natural killer cell mediated anti-tumor responses

Int J Hyperthermia

In situ tumor ablation creates an antigen source for the generation of antitumor immunity

Cancer Res

Activation of tumor-specific T lymphocytes by radio-frequency ablation of the VX2 hepatoma in rabbits

Cancer Res

Radiofrequency thermal ablation of hepatocellular carcinoma liver nodules can activate and enhance tumor-specific T-cell responses

Cancer Res

Efficient loading of dendritic cells following cryo and radiofrequency ablation in combination with immune modulation induces anti-tumour immunity

Br J Cancer

RFA strongly modulates the immune system and anti-tumor immune responses in metastatic liver patients

Int J Oncol

NK-cell recognition

Annu Rev Immunol

Surface NK receptors and their ligands on tumor cells

Semin Immunol

Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/neu-positive metastatic breast cancer

J Clin Oncol

Two immunoglobulin G fragment receptors polymorphisms independently predict response to rituximab in patients with follicular lymphoma

J Clin Oncol

Natural killer cell receptors and their ligands in liver diseases

Med Mol Morphol

Liver: an organ with predominant innate immunity

Hepatology

Hepatic natural killer cells exclusively kill splenic/blood natural killer-resistant tumor cells by the perforin/granzyme pathway

J Leukoc Biol

Basic—Liver, Pancreas, and Biliary Tract
Radiofrequency Thermal Ablation for Hepatocellular Carcinoma Stimulates Autologous NK-Cell Response